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A brief introduction of depression
Mood disorders and in particular major depression, remain one of the most prevalent psychiatric disorders with a lifetime prevalence rate over 16% and affects twice as many women as men. The clinical use of the word “depression” is normally restricted to major depressive disorder (MDD). According to the Diagnostic and Statistical Manual (DSM), MDD is diagnosed when the two major symptoms: depressed mood and anhedonia, or inability to feel pleasure, and at least two of the following eight symptoms are present for at least two weeks: decreased self-esteem, guilt feelings,impaired memory and concentration, increased fear and anxiety, insomnia or hypersomnia, increased or decreased appetite, general retardation or agitation and repetitive pre-occupation with death, with or without suicidal plans. In contrast, dysthymia, or minor depression, is diagnosed when only some of these symptoms are present. In addition, depression due to a general medical condition (DGMC) is diagnosed when the above-mentioned symptoms result from severe somatic illness, trauma, ordisability and postpartum depression (PD) which appears immediately or shortly after child-birth.
Regulation of G-protein coupled receptor signalling underpinning neurobiology of depression
G protein-coupled receptors (GPCRs) are the largest class of cell surface membrane proteins in the human genome. About 800 GPCRs have been identified in the human, half of which exhibitsensory functions. Mammalian GPCR regulation involves more than 20 RGSs that act as scaffolding proteins and interact directly and selectively with GPCRs to determine the magnitude and duration of GPCR signaling and cellular responses. The importance of RGS protein modulation of receptor signaling in anxiety and depression was first suggested in rodent experiments that linked Rgs2 gene expression levels with anxiety and depression, and demonstrated that mice with reduced expressionlevels of RGS2 exhibit increased depressive-like and anxiety-like behaviors. Another member of the RGS family, RGS6 present in abundance in hippocampal and cortical neurons, has been shown to modulate Gai/o protein activity, which is critically important in the CNS for neuronal responses to a wide array of GPCRs and their cognate neurotransmitters. A number of studies identified RGS6 as animportant regulator of brain GPCR cascades involved in the neurobiology of depression.
GPCRs function and underpin the pathological basis of depression (Grammatopoulos D K., 2017)
Current strategies in the treatment of depression
Role of GPCR
GPCRs are the target of approximately half of all therapeutic drugs. GPCRs are sub-divided into three categories based on coupling-type: GαS, GαI/O and GαQ/Z. Activation of GαS and GαI-coupledreceptors leads to either activation or inhibition of adenylate cyclase (AC) and alters intracellular cyclic adenosine monophosphate (cAMP) levels. Cyclic AMP activates protein kinase A (PKA) which in turn triggers transcription factors including the cAMP response element binding protein (CREB) . This builds on cAMP responsible element (CRE) chromosome areas, activating specific gene transcription. One gene regulated by this pathway is for brain derived neurotrophic factor, BDNF which is reported to have a central role in adult hippocampal neurogenesis, neuronal survival and plasticity and also in stress reaction, depression, antidepressant drug response and electroconvulsive therapy.
G protein-coupled receptor kinases (GRKs) and β-arrestins
Altered expression of GRKs can be detected also in peripheral blood cells and these changes seem to mirror the clinical status and also effectiveness of antidepressants. In platelets, for example, theconcentration of GRK2 in depressed patients decreases in parallel with an up-regulation of a2A-adrenoreceptors, and the severity of depression in un-treated patients inversely correlates with the GRK2 platelet concentration. In depression, the activity of multiple GPCRs is altered following antidepressant treatment. GRKs and arrestins, as major regulators of GPCR signaling, have been implicated in the mechanisms of depression and actions of antidepressant drugs. Rodent experiments showed that β-arrestin-1 levels are significantly elevated by different antidepressants in rat cortex and hippocampus. Similar changes can be detected in mononuclear leukocytes of patients with depression that show significantly reduced immunoreactive quantities of β-arrestin-1 suggesting a potential role as a biochemical marker for depression.
G protein-coupled receptor (GPCR) heterodimerization
A new strategy may be to search for specific pathways involved in disease pathophysiology that is mediated by receptor-receptor interactions rather than the receptors themselves. The development of molecules that will be able to enhance or block specific receptor pairs may potentially improve the treatment of depression. There is evidence that GPCR heteromers may play a crucial role in psychiatric disorders. Recent data suggest that serotonin 5-HT2A and glutamate mGlu2 receptor heteromers might be a promising new target for the treatment of psychoses. Gonzales-Maeso and coworkers have shown that the 5-HT2A-mGlu2 heteromer might be involved in altered cortical function in patients with schizophrenia. Their studies showed that the 5-HT2A-mGlu2 complex may integrate serotonin and glutamate signaling and modulate G protein coupling. The heteromers, such as Gal-5-HT1A, D1-D2receptor heteromers, 5HT1A-5HT7 receptor heteromers, and CRH1-V1b receptor heteromers, with their unique pharmacological and functional properties, are likely to lead to novel effective strategies in the development of antidepressant drugs.
Conclusions and expectation
Depression and mood disorders remain severe diseases associated with significant morbidity and mortality, and long-term burden to society. Although GPCRs play well-established roles inthe pathophysiology of depression and are recognized targets in the search for more specific and effective pharmacological approaches, our understanding of the specific mechanisms of action and regulatory pathways remains limited. Elucidating the complex systems of GPCRs will allow the design of novel therapeutic strategies and selective pharmaceutical agents that are clinically effective especially for patients with refractory illnesses to conventional medications and overcome off-target actions and undesired side effects.
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